sparteine i-PrLi, Et Asymmetric Deprotonation · Cox and Simpkins, "Asymmetric Synthesis Using...
Transcript of sparteine i-PrLi, Et Asymmetric Deprotonation · Cox and Simpkins, "Asymmetric Synthesis Using...
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Asymmetric Deprotonation
Fe
O
Fe
O
N(i-Pr)2
1. n-BuLi (–)-sparteine Et2O, -78°C
2. Ph2PCl
PPh2
N(i-Pr)2 90% ee
David Ebner
Stoltz Group Literature Presentation
March 28, 2005
N
Ph
Li
CF3NO
t-Bu
OTMS
t-Bu
TMSCl, HMPATHF, -100°C
93% ee
Ligands, Bases, and Applications
O
OHH
H
84% ee(–)-sparteine
i-PrLi, Et2O, -98°C
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Enantioselective Deprotonation
Reaction Pathways
R R'
Ha Hb base
- Ha
- Hb
R R'
M Hb
R R'
Ha M
electrophile
electrophile
R R'
E Hbretention
inversion
retention
inversion
R R'
Hb E
R R'
Ha E
R R'
E Ha
possibleanion
inversion
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Enantioselective Deprotonation
Reaction Pathways
R R'
Ha Hb base
- Ha
- Hb
R R'
M Hb
R R'
Ha M
electrophile
electrophile
R R'
E Hbretention
inversion
retention
inversion
R R'
Hb E
R R'
Ha E
R R'
E Ha
possibleanion
inversion
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Enantioselective Deprotonation
What Will NOT Be Covered
R R'
Ha Hb base
- Ha
- Hb
R R'
M Hb
R R'
Ha M
electrophile
electrophile
R R'
E Hbretention
inversion
retention
inversion
R R'
Hb E
R R'
Ha E
R R'
E Ha
possibleanion
inversion
Great Chemistry Not Covered Today:- Chiral Auxiliary-Directed Deprotonation- Enantioselective Additions of Achiral Anions to Chiral or Homochiral Electrophiles • Aldols • Carbolithiations • Achiral Alkyllithium Additions to Electrophiles- Enantioselective Reactions of Racemic or Equilibrating Anions • Deprotonation Adjacent to S, P, Se, Ph (usually) • Wittig Rearrangements
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Enantioselective Deprotonation
Outline and Key Players
I. meso-Ketone Deprotonations
II. meso-Epoxide Deprotonations
a. -Deprotonation
b. -Deprotonation
III. Deprotonation Adjacent to Heteroatoms
a. O: Alkyl and Allylic Systems
b. N: Alkyl, Benzylic, and Allylic Systems
IV. Other Enantioselective Deprotonations
a. Elimination of HX
b. Aromatic Lithiation
General Reviews:
1. Majewski, "Enantioselective Deprotonation of Cyclic Ketones," in Advances in Asymmetric Synthesis, Vol. 3, pp 39-76, JAI Press, London:
1998.
2. Waldmann, "Enantioselective Deprotonation and Protonation," in Organic Synthesis Highlights II, H. Waldmann, ed. pp 19-28, VCH, Weinheim:
1995.
3. Organolithiums in Enantioselective Synthesis, D. Hodgson, ed. Springer, New York: 2003. (Whole book is good, especially pp 61-286.)
4. O'Brien, "Recent Advances in Asymmetric Synthesis Using Chiral Lithium Amide Bases," J. Chem. Soc., Perkin Trans. 1, 1998, 1439-1457.
5. Hoppe and Hense, "Enantioselective Synthesis with Lithium/(–)-Sparteine Carbanion Pairs," Angew. Chem. Int. Ed. Engl. 1997, 36, 2282-2313.
6. Hodgson, Gibbs, and Lee, "Enantioselective Desymmetrisation of Achiral Epoxides," Tetrahedron, 1996, 52 (46), 14361-14384.
7. Cox and Simpkins, "Asymmetric Synthesis Using Homochiral Lithium Amide Bases," Tetrahedron: Asymmetry, 1991, 2 (1), 1-26.
8. Eames, "Recent Developments in Enantioselective Deprotonation Mediated by Sub-Stoichiometric Quantities of Chiral Bases," Eur. J. Org.
Chem., 2002, 393-401.
9. Beak, Basu, Gallagher, Park and Thayumanavan, "Regioselective, Diastereoselective, and Enantioselective Lithiation-Substitution Sequences:
Reaction Pathways and Synthetic Applicaitons," Acc. Chem. Res. 1996, 29, 552-560.
K. Koga
Tokyo
Ketones
N. Simpkins
Nottingham
Ketones and Aromatics
M. Majewski
Saskatchewan
Ketones
D. Hodgson
Oxford
Epoxides
D. Hoppe
Muenster
Heteroatoms: O
P. Beak
Illinois, Urbana-Champaign
Heteroatoms: N
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R
O
R
O
HH
ProtonsDifferentiatedby Chiral Base
H H Li-amideBase
(Additives)
R
O
HH
LiLn
NR'R''
R
O
H
LnLi
NH
R'
R''
E+
R
OE
H
OR
R
O
H E
Asymmetric Deprotonation of meso Cyclic Ketones
General Considerations
O
HHR Li-amide
Base
(Additives)?
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Chiral Lithium Amides Used in Ketone Deprotonations
Only a Few of the Many!
Ph N
Li
Ph Ph N
Li
Me
N
Li
Me
Ph N
Li
CF3
H
NPh
LiN
Ph
N
Ph
Li LiPh Ph
N
Ph
Li
t-Bu
N
Ph
Li
CF3
H
NPh
Li
N
Ph
Li
N
N
N
N
H
N
Li
Ph
N
Li
Ph
N
N
Li
NLi
NN
Li
Ph Ph
NPh
Li
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Prochiral 4-Substituted Cyclohexanones
Enantioselective Deprotonation of Simple Substrates
Ph N
Li
PhN
Ph
Li
CF3N
O
R
OTMS
R
Li-amideTMSCl
HMPATHF, -100°C
% Yield % eeR
Me
i-Pr
t-Bu
Ph
76 94
92 95
95 93
88 93
O
t-Bu
OTMS
t-Bu
Li-amideTMSCl
THF
Temp (°C) Quench % eeLiCl (equiv)
-78
-90
-78
-78
Internal
Internal
External
External
0
0
0
0.5
69
88
23
83
Koga, et. al. Tetrahedron 1997, 53, 13641 Simpkins, et. al. J. Chem. Soc., Perkin Trans. 1 1993, 3113
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Tropinone Derivatives
Different Conditions and Electrophiles Lead to a Variety of Products
Majewski, et. al. Tetrahedron Lett. 1994, 35, 3653 Tetrahedron Lett. 1995, 36, 5465
N
O
NN
Ph
Li
t-Bu
LiCl, THF, -78°C
N
OLi95% ee
N
OHOH
Ph
PhCHO MeO2CCNN
OMeO2C H
ClCO2Bn
O
N
BnO2C
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Other Prochiral Cyclic Substrates
Similar Ligands Yield Good ee's with a Variety of Electrophiles
Ph N
Li
Ph
O
OTMS84% ee
60% ee
O O
t-Bu
OOHH
OTMSBnO
96%84% ee
OTMSPh
81%71% ee
N
Li
OTMSTBSO
90%90% ee
OTMSn
n = 3: >99% een = 5: 95% ee
N
Li
t-Bu
Ph
N
N
OTMS
62%85% ee
O
O
97% ee
CO2MeOTESPh
67%92% ee
Ph N
H
H
OTMSO
O
95%83% ee
N OO
Ph
TMSH
72%91% ee
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Catalytic Asymmetric Ketone Deprotonations
Early Efforts Lead to Moderate Selectivity
Koga, et. al. Tetrahedron 1997, 53, 1698
O
R
OTMS
R
1. Base, THF, -78°C HMPA (2.4 equiv)
2. TMSCl
N
Ph
Li
CF3N
% Yield % eeR
Me
i-Pr
t-Bu
Ph
78
75 79
77 80
85 81
NN N
Li
1.2 equiv
2.4 equiv
0.3 equiv
1.5 equiv DABCO
% Yield % ee
70 75
80 76
77 76
83 79
N
Ph
H
CF3N
Stoichiometric, 1 h Catalytic, 1.5 h
82
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Chiral Magnesium Amides in Ketone Deprotonation
Less Reactive Alternative to Lithium Amides
Ph N Ph2
Mg
O
R
HMPA (0.5 equiv), TMSClTHF, -78°C, 6 h
OTMS
R
% Conv. % eeR
Me
i-Pr
t-Bu
Ph
81 82
77 90
79 74
82 82
n-Pr 88 76
O
i-Pri-Pr Ph N Ph2
Mg
HMPA (0.5 equiv)TMSCl, THF
OTMS
i-Pri-Pr
Temp (°C) Time (h) % ee% Conv.
-78
-60
-40
rt
39
6
6
2
54
66
99
100
>99
99.4
98.8
82
i-Pr i-Pr
O
(±)-
i-Pr i-Pr
OTMS
i-Pr i-Pr
O
+Ph N Ph
2Mg
HMPA (0.5 equiv), TMSClTHF, -40°C, 67 h
66%, 62% ee 34%, 88% ee
Kerr, Henderson, et. al. Tetrahedron, 2002, 58, 4573
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Deprotonation of Epoxides
Early Surprising Results
OLiNEt2
Et2O,
H
H
OH
OHCHO + +
55-60% 10-15%32%
Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849
OOLiNEt2
Et2O, -10°C
95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158
H
H
OH
HB:
H
H
OH
H
B:
H
H
O
:B
H
H
H
O
:B
H
H
H
O
H
H
O
B:
H
OH
H
O
B:
H
O
H :BProposedMechanism:
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Deprotonation of Epoxides
Early Surprising Results
OLiNEt2
Et2O,
H
H
OH
OHCHO + +
55-60% 10-15%32%
Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849
OOLiNEt2
Et2O, -10°C
95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158
H
H
OH
HB:
H
H
OH
H
B:
H
H
O
:B
H
H
H
O
:B
H
H
H
O
H
H
O
B:
H
OH
H
O
B:
H
O
H :BProposedMechanism:
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Deprotonation of Epoxides
Early Surprising Results
OLiNEt2
Et2O,
H
H
OH
OHCHO + +
55-60% 10-15%32%
Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849
OOLiNEt2
Et2O, -10°C
95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158
H
H
OH
HB:
H
H
OH
H
B:
H
H
O
:B
H
H
H
O
:B
H
H
H
O
H
H
O
B:
H
OH
H
O
B:
H
O
H :BProposedMechanism:
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Deprotonation of Epoxides
Early Surprising Results
OLiNEt2
Et2O,
H
H
OH
OHCHO + +
55-60% 10-15%32%
Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849
OOLiNEt2
Et2O, -10°C
95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158
H
H
OH
HB:
H
H
OH
H
B:
H
H
O
:B
H
H
H
O
:B
H
H
H
O
H
H
O
B:
H
OH
H
O
B:
H
O
H :BProposedMechanism:
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Deprotonation of Epoxides
Early Surprising Results
OLiNEt2
Et2O,
H
H
OH
OHCHO + +
55-60% 10-15%32%
Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849
OOLiNEt2
Et2O, -10°C
95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158
H
H
OH
HB:
H
H
OH
H
B:
H
H
O
:B
H
H
H
O
:B
H
H
H
O
H
H
O
B:
H
OH
H
O
B:
H
O
H :BProposedMechanism:
H
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Asymmetric Deprotonation of Epoxides
Can Reactivity Be Controlled?
–H –H
RLiAddition
–Li2O
O
HH
O
Li
OLiOLi
OLi
Li
R
R
O
E
OLi OLiOLi
ElectrophileTrapping
ReductiveAlkylation
1,2-HydrideShift
C-H or C=CInsertion
C-HInsertion
Electrocyclic-Ring Opening
Hodgson and Gras, Synthesis, 2002, 12, 1625
Base
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Asymmetric ß-Deprotonation of Epoxides
Allylic Alcohols Using Lithium Aminoamide Bases
N
N
LiO
OH
77%79% ee
THF, 0°C
TBSO O TBSO
OH
TBSOO
C16H33
TBSO OH
C16H33
92%90% ee
75%89% ee
Ph
NLi
N
PhH, 0°C30 h
O
N
H
Li
HN
H
O
N
H
Li
HN
H
Favored Disfavored
Asami, et. al. Tetrahedron, 1995, 51, 11725
Singh, et. al. J. Org. Chem, 1996, 61, 6108
TBSO O TBSO
OH
66%97% ee
Li amide
PhH, 4°C
Li amide
PhCH3, 0°C
Proposed Selectivity Model:
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Asymmetric ß-Deprotonation of Epoxides
Use of Commercially-Available Ephedrine-Based Aminoalcohols
R O R
R = OBn 91%, 86% eeR = CH2OH 57%, 95% ee
Hodgson, et. al. Tetrahedron: Asymmetry, 1996, 7, 407
OH
Ph
LiHN OLi
O
R = Me 63%, 99% eeR = Bu 67%, 96% eeR = BnOCH2 76%, 89% ee
Ph
LiHN OLi
HO
R
OHHO
R
Murphy, et. al. J. Chem. Soc., Chem. Commun., 1993, 884
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Catalytic Asymmetric Examples
Recent Studies Allow Similar Levels of Selectivity
Andersson, et. al. J. Am. Chem. Soc., 1998, 120, 10760
Asami, et. al. Tetrahedron: Asymmetry 1994, 5, 793 Tetrahedron Lett. 1997, 38, 6425
O
OH
N
N
LiN
N
LiH
H
Li amide (20 mol %)
LDA, THF, rt
+ 1 equiv LDA + 6 equiv DBU12 h, 71%, 75% ee
+ 1.8 equiv LDA6 h, 95%, 88% ee
n
NHN
catalyst (5 mol%)
n = 1 91%, 96% een = 2 89%, 96% een = 3 81%, 78% ee
O
nOHLDA (2 equiv)
THF/DBU (95:5)0°C, 24 h
NH H
O
OH
catalyst (20 mol%)
LDA (1.25 equiv)THF, 0°C, 15 h
Li
77%95% ee
Malhotra, Tetrahedron: Asymmetry, 2003, 14, 645
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Enantioselective -Deprotonation of Epoxides
Transannular C-H Insertion With Alkyllithium Diamine Complexes
(–)-sparteine (2.5 equiv)
i-PrLi (2.4 equiv)Et2O, -98°C to rt, 20 h
Hodgson, et. al. J. Chem. Soc., Perkin Trans 1, 2001, 2161
O
O
O
OHH
H
H
H
OH
H
H
OH
86%84% ee
77%83% ee
97%77% ee
BocN O
N
OHO
Ot-Bu
(–)- -isosparteine (24 mol %)
i-PrLi (2.4 equiv)Et2O, -98°C, 40 h
NN
NN
N
OLi
Boc
NBoc
O
Li
Hodgson and Lee, Chem. Commun. 1996, 1015
54%, 89% ee
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More Transannular Epoxide Rearrangements
Reactivity Differences in Bicyclic Systems
Hodgson and Marriott,Tetrahedron: Asymmetry, 1997, 8, 519
Li amideEt2O
0°C to rt
NN
O
O
HH
HH
Ph N
Li
Ph
chiral baseOH
H
Ph N
Li
PhO
40%, 32% ee 20%, 38% ee
OH
H
+
O
HLiH
OLi
H
HydrideShift
O
LiH
H
OLi
Ha
Hb
HaShift Hb
Shift
(–)-sparteines-BuLi
pentane-78°C to rt
73%, 49% ee 73%, 52% ee
HaHb
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Trapping of Lithiated Epoxides
Enantioselective Epoxide Substitution with Various Electrophiles
Hodgson, et. al. Org. Biomol. Chem. 2003, 1, 4293
O
Conditions
s-BuLi (1.25 equiv)(–)-sparteine (1.3 equiv)
Et2O, -90°C, 3 hthen
electrophile (1.5 equiv)-90°C to rt over 5 h
O
TMSO
O
OO
SnR3
OO
O
HO
PhO
Ph
HO
Et
HO
Et
EtO
Et
O
OEt
72%, 74% ee
R = Bu; 72%, 74% eeR = Me; 65%, 78% ee
58%, 81% ee 75%, 77% ee
74%, 76% ee
68%, 77% ee80%, 76% ee
67%, 78% ee
EtCONMe2
PhCHO
EtCHOR3SnCl
PhCONMe2TMSCl
Et2COEtOCOCl
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Deprotonation Adjacent to Heteroatoms
A Return to Reaction Pathways
R X
Ha Hb base
- Ha
- Hb
R X
M Hb
R X
Ha M
electrophile
electrophile
R X
E Hbretention
inversion
retention
inversion
R X
Hb E
R X
Ha E
R X
E Ha
R = Ph (usually)X = S, P, Se, etc.
Asymmetric Deprotonation Adjacent to Heteroatoms
• X = O, R = Alkyl
• X = CH=CR'OR'', R = Aryl, Alkyl
• X = N, R = Alkyl, Aryl, Allyl
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Deprotonation Adjacent to Oxygen
Alkyl Carbamates
OCbyR
HS HR
1. s-BuLi (–)-sparteine
2. Electrophile
OCbyR
EN
O
OCby =
OCbyMe
E
E % Yield % ee
86 > 96
PbMe3 61 93
CH2CH=CH2 60 42
D
OCbyR
Me
% Yield % ee
60 98
64 92
85 > 95
H3C(CH2)11
R
CbyO
OCby
E
E % Yield % ee
56 > 95
Bu3Sn 70 > 95
Me3Si 70 > 95
CO2Me
Bn2N
Me 72 > 95
FeOCby
PPh2
80%> 95% ee
TBSO OCby
SnBu3
85%> 95% ee
CbyO OCby
CO2Me
80%> 95% ee
Hoppe, et. al. Angew. Chem., Int. Ed. Engl. 1990, 29, 1422 Angew. Chem., Int. Ed. Engl. 1992, 31, 1505 Synthesis 1999, 1573 Org. Lett. 2002, 4, 2189
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Asymmetric Deprotonation of Alkyl Carbamates
Intramolecular Reactionss-BuLi
(–)-sparteine
Et2O-78°C to rt
N
O
OCby =
Hoppe, et. al. Synlett 1994, 1034
Ph O N(i-Pr)2
O
Ph
OH
O
N(i-Pr)2
Ph O N(i-Pr)2
OLi
PhO
H OLi
N(i-Pr)2
-78°C to rt
46%96% ee
Tomooka, Shimizu, Inoue, Shibata,l Nakai, Chem. Lett. 1999, 759
CbyO OCby
Li(sparteine)
CbyO OCby
s-BuLi(–)-sparteine
Et2O, -78°C
TMSClor ZnCl2
TBSOTfor BF3•OEt2
H
OCby
> 95% ee
OCby
H
74% ee
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Silyl Alkenyl Carbamates
Configurationally Stable Allyllithiums
Hoppe, et. al. Org. Lett. 2004, 6, 783
Ph TMS
OCbxE
TMS
OCbxE
E % Yield % ee
85 95
Bu3Sn 80 95
MeOC(O) 35 72
Me3Si
E % Yield % ee
18 92
Bu3Sn 61 95
Ph3Sn 96 95
Me3Si
t-BuC(O) 66 83
Ph3Sn 83 95
Ph TMS
OCbxE
E % Yield % ee
72 95
t-BuC(O) 94 95
Me2COH 92 95
MeOC(O)
R TMS
OCbxH H
n-BuLi(–)-sparteine
PhCH3, -78°C
R TMS
O
O
Li
(i-Pr)2N
R TMS
OCbxE
OCbx = N(i-Pr)2
O
R = Ph
Ph TMS
OCbxLi
Ph TMS
OCbxR' R'
O
HO R'R'
electrophile
82 90cC6H11OH
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Enantioselective Homoaldols
Metal Exchange to Ti Leads to a Highly Diastereoselective Process
R TMS
OCbxH H
n-BuLi(–)-sparteine
PhCH3, -78°C
R TMS
O
O
Li
(i-Pr)2N
R' % Yield % ee
70 95
72 95
cC6H11 69 95
CH3(CH2)2
71 89
TMS
OCbxMe
R'
OH
OCbx = N(i-Pr)2
O
TiCl(NEt2)3 RTMS
Ti(NEt2)3OCbx
R'CHO
R'
OH
R
TMS
OCbx
(CH3)2CH
C6H5
80 95(CH3)3C
R' % Yield % ee
98 91
95 94
cC6H11 93 97
CH3(CH2)2
99 95
TMS
OCbxPh
R'
OH
(CH3)2CH
4-BrC6H4
98 95(CH3)3C
Hoppe, et. al. Org. Lett. 2004, 6, 783
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Deprotonation Adjacent to Nitrogen
Alkyl Carbamates Revisited
N
Boc
N
s-BuLi(–)-sparteine
Et2O, -78°C
N
Boc
HR
HS
HS
HR
Li electrophileN
Boc
E
Ot-BuO
E % Yield % ee
88 94
Me3Si 71 94
Bu3Sn 83 96
Me
CO2H 55 88
N
N
Boc
E N
Boc
E
40-50%0-88% ee
15-70%94-98% ee
Beak, et. al. J. Org. Chem. 1997, 62, 7679Coldham, et. al. Org. Lett. 2001, 3, 3799
Beak, et. al. J. Am. Chem. Soc. 1994, 116, 3231
N
Boc
1. CuCN•LiCl
2. alkenyl iodideLi N
Boc R1
R2
R3
Dieter, et. al. J. Am. Chem. Soc. 2001, 123, 5132
89-95%86-90% ee
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Benzylic Carbamates
Configurationally Stable Benzyllithiums Possible
% Yield % ee
81 94
Et 78 94
Me
Beak, et. al. J. Am. Chem. Soc. 1996, 118, 3757
PhX
chiralbase
PhX
M*enantioselective
electrophile
substitution PhX
EMost Benzylic
Deprotonations:
Configurationally
Unstable Anions
PhNAr
chiral base
enantioselectivedeprotonation
PhNAr
M* electrophilesubstitution
PhNAr
EX = NArBoc:
Enantiomeric Anions
Do Not Interconvert
at Low Temp!
BocBoc Boc
MeO
N
Boc
Ph HN
Boc
Ph
R1. n-BuLi (–)-sparteine
2. ROTf3. CAN
R
69 93
Bn 73 96
Allyl
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More Benzylic Carbamates
Applications and Electrophiles
Beak, et. al. J. Am. Chem. Soc. 1997, 119, 10537 J. Org. Chem. 1999, 64, 2996
N
Boc
Ph
1. n-BuLi (–)-sparteine
2. Michael AcceptorN
Boc
Ph
E
Ph
N
Ar
BocO
R
R = H: 72%, 94% ee
R = Me: 63%, 94% ee
Ph
N
Ar
Boc
n = 1: 86%, >99:1 dr, 92% ee
n = 2: 82%, >99:1 dr, 92% ee
O
n
Ph
N
Ar
Boc
91%, 92:8 dr, 90% ee
PhNC
CN
Ar = p-MeOC6H4Ar Ar
N
Boc
Ar
s-BuLi(–)-sparteine
PhCH3, -78°C
ClN Ar
Boc
% Yield % ee
72 96
1-Naphthyl 68 92
Ph
Ar
52 92
3-furyl 21 96
3-thienyl
Beak, et. al. J. Am. Chem. Soc. 1996, 118, 715
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Lithium Amides in Benzylic Deprotonation
Cyclization of Arylamides Leads to Isoindolones
Clayden, et. al. Tetrahedron 2002, 58, 4727 J. Am. Chem. Soc. 2005, 127, 2412
MeO
N
O
Ph
Ph MeO
N
O
Ph
PhLi
-78 to 0°C
MeO
N
OLi
PhPhH
1. NH4Cl, H2O2. HCl, H2O
O
N
O
PhPhH
H
Ph N
Li
88%, 81% ee
NH
CO2HCO2H
(–)-kainic acid
NH
CO2HCO2H
HO2C(–)-isodomoic acid C
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Enantioselective N-Allylcarbamate Deprotonation
Beak, et. al. J. Am. Chem. Soc. 1996, 118, 12218 J. Am. Chem. Soc. 2001, 123, 1004
Ph
NAr Boc
Ph H
NLiBocAr
n-BuLi(–)-sparteine electrophile
Ph
NAr Boc
EAr = p-MeOC6H4
% Yield % ee
73 94
Bn 70 96
Me
E
Allyl 72 94
R
NAr Boc
1. n-BuLi (–)-sparteine
2. Carbonyl or Michael Acceptor
R
ArNBoc
HO
R' R''
ArNBoc
77%, 98% ee
Ph
OH
ArNBoc
80%, 86% ee90:10 dr
Ph
N
O
ArNBoc
62%, 96% ee80:20 dr
Me
O
ArNBoc
80%, 92% ee89:11 dr
Ph
O
O
Boc
ArNBoc
80%, 88% ee63:44 dr
Ph
Cy
NC
ArNBoc
86%, 96% ee94:6 dr
Ph
Ph
EtO2C
ArNBoc
73%, >94% ee98:2 dr
Ph
i-Bu
O2N
CNEtO2C
ArNBoc
R
R'
R''
OH
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Enantioselective Synthesis by Loss of HX
Chiral Amides Lead to Enantioenriched Alkenes
Duhamel, et. al. Tetrahedron: Asymmetry, 1990, 1, 347
H
H
X OTf
Ph N
Et2O, -70°CH
H
X
X = O 44% ee
X = –O(CH2)2O– 99% ee
Sakai, et. al. Tetrahedron Lett. 1987, 28, 6489
R
Cl
HO2C
N
Li
Ph
THF, -78°C
R
HO2C
R = Me 80% ee
R = t-Bu 82% ee
Me
Cl
N
Li
Ph
THF, -78°C
Me
75% ee
CO2H CO2H
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More Enantioselective Loss of HX
Chiral Alkoxides Allow Catalytic Reactions
Duhamel, et. al. J. Org. Chem., 1998, 63, 5541
OO
BrR
Br Ph
HO
NMe2
(10 mol %)
MeOH (4 mol %)KH, THF
-80°C, 72 h
OO
R
Br
H
% Yield % ee
83 90
n-Pr 78 77
t-Bu
R
79 65
p-PhC6H4 81 96
i-Pr
Ph 82 94
79 >98p-MeOC6H4
78 >98p-NO2C6H4
KH
H2
2.5 equiv4 mol %
MeOH
MeOK
10 mol %
Ph
K+ -O
NMe2
Ph
HO
NMe2
OO
BrR
Br
OO
R
Br
H
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Enantioselective Lithiation of Aromatics
Generation of Planar Chirality with Lithium Amide Bases
Simpkins, et. al. J. Chem. Soc., Perkin Trans 1, 1997, 401
Ph N
Li
Ph
Fe
PPh2
O
TMSCl, THF-78°C
Fe
PPh2
O
TMS95%
54% ee
Simpkins and Price, Tetrahedron Lett., 1995, 36, 6135
OMe
Cr(CO)3
Ph N
Li
Ph
LiCl, THF-78°C, 15 min
OMe
Cr(CO)3
Li
OMe
Cr(CO)3
OH
PhPhCHO 67%
65% ee
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Enantioselective Lithiation of Aromatics
Generation of Planar Chirality with Alkyllithium / Sparteine
Uemura, et. al. Tetrahedron: Asymmetry, 1994, 5, 1427
Fe
O
Fe
O
Snieckus, et. al. J. Am. Chem. Soc., 1996, 118, 685
N(i-Pr)2
1. n-BuLi (–)-sparteine Et2O, -78°C
2. electrophile
E
N(i-Pr)2
% Yield % ee
96 98
Me 91 94
TMS
E
Ph2C(OH) 91 99
85 96
Ph2P 82 90
I
89 85B(OH)2
O
Cr(CO)3
t-BuLiPhCH3, -78°C
Ph2PCl 85%75% ee
Ph
Me2N NMe2
Ph
O
Cr(CO)3
Li
O
Cr(CO)3
PPh2
N
O
O
O
N
O
O
N
O